PROJECT SUMMARY Device-based ablation of renal nerves has emerged as a non-pharmacological therapy for patients with treatment-resistant hypertension. Recent clinical trials demonstrate it decreases arterial pressure in most patients with treatment-resistant hypertension, but the neuronal mechanisms mediating this effect are unknown. This procedure non-selectively destroys both the sensory and sympathetic nerves of the kidney, and despite its promise, some patients experience a rise, rather than a fall in arterial pressure. One explanation for this heterogeneity of responses is that different populations of renal nerves play different roles in regulation of arterial pressure. For example, the extent to which these renal sympathetic and sensory nerves contribute to hypertension is unclear. The current dogma is that renal sensory nerve fibers are located mainly in the wall of the renal pelvis and reflexively inhibit sympathetic nerves. This is consistent with the observation that ablation of these nerves increases arterial pressure in some trials. However, we recently established that renal sensory nerves also reflexively excite sympathetic nerves, with a decrease in arterial pressure and sympathetic pressor activity following a sensory-specific chemical renal denervation in the DOCA-salt rat model of renal inflammation and hypertension. The anatomical distribution of sensory nerves within the kidney has not been extensively studied, and I have observed abundant sensory fiber localization near the cortical glomeruli of mouse, rat, and pig kidney that remains largely unreported. There remains a gap in our knowledge of the extent and targets of this sensory innervation of the renal cortex, and the function of cortical sensory fibers in the modulation of sympathetic activity. My project aims to investigate these gaps with two complementary goals in both healthy and DOCA-salt hypertensive mice. First, I will use the tissue-clearing CLARITY procedure, followed by immunofluorescence to determine the extent of the innervation of glomeruli by sensory fibers. Second, I will stimulate these sensory fibers within the renal cortex using optogenetics to determine the roles they play in controlling arterial pressure and kidney function. Based on preliminary results and current literature, my central hypothesis is that sensory fibers innervate cortical glomeruli and regulate renal function through a sympatho- excitatory reflex, which is amplified in DOCA-salt HTN. The results of these experiments will lead to a more complete understanding of sensory renal neuroanatomy and the influences sensory fibers on renovascular hypertension. Should these sensory fibers located in the cortex prove to function in a sympatho-excitatory manner, they would represent a promising target for ablation to enhance the anti-hypertensive effects of renal denervation therapies. This furthers our long-term goal of expanding our understanding of the role of renal nerves in the development and maintenance of hypertension to help guide ablative and neuromodulatory renal nerve- based treatments.